Thyroid hormone receptors (TRs) are essential for growth, differentiation, and development. There are two TR genes, alpha and beta, which yield four thyroid hormone (T3) binding isoforms-TR alpha 1, TR beta 1, TR beta 2, and TR beta 3. Given the critical roles of TRs in cellular functions, it is reasonable to expect that mutations of TRs could have deleterious effects. Indeed, mutations of the TR beta gene are known to cause a human genetic disease, thyroid hormone resistance syndrome (RTH). For the past several years, we have been using the powerful tool of mouse genetics to elucidate the molecular basis of RTH, to uncover diseases due to mutations of TRs and to understand the molecular mechanisms of thyroid hormone action in vivo. The TR beta PV mouse is a valid model of a human disease, resistance to thyroid hormone (RTH) RTH is a disease due to mutations of the TR beta gene. We created a knockin mutant mouse by targeting a mutation (PV) into the TR beta gene via homologous recombination and the Cre-loxP system (TR beta PV mouse). TR beta PV mice faithfully reproduce the human RTH. Through use of this mouse model, it has become possible, for the first time, to address several critical, clinically relevant issues. We have shown that RTH symptoms are caused by the interference of mutant TR beta with the transcriptional activity of wild-type TR alpha 1 and TR beta in vivo. We have also discovered that variable phenotypic expression in RTH patients is dictated by tissue-dependent abundance of TR beta and TR alpha 1 isoforms, by the promoter context of T3 target genes, and by tissue-dependent expression of co-activators such as the steroid hormone receptor coactivator-1 (SRC-1) and SRC-3. In addition, we have found that the mild phenotype frequently observed in heterozygous RTH patients is due to the compensatory effect of wild-type TR alpha 1. Using the TR beta PV mouse model, we have further delineated the molecular mechanisms by which mutations of TR beta lead to the manifestation of pathological phenotypes at the transcriptional level. Using mouse arrays consisting of 11,500 genes and multi-tissue analyses, we have uncovered complex multiple signaling pathways that mediate the molecular actions of TR beta mutants in vivo. Particularly, the T3-independent mutant-dependent genomic response unveiled the contribution of a novel "change-of-function" of TR beta mutants to the pathogenesis of RTH. These findings revealed that the molecular actions of TR beta mutants are more complex than previously envisioned. Based on the mouse model findings, not only can better treatments for RTH be developed but also better management of other receptor diseases can be envisioned. The TR betaPV/PV mouse is a unique model to dissect the molecular genetics underlying thyroid carcinogenesis That mutations of the TR beta gene also cause diseases other than RTH was discovered by the spontaneous development of follicular thyroid carcinoma in TR betaPV/PV mice. Similar to human thyroid cancer, thyroid carcinoma of TR betaPV/PV mice progresses with sequential capsular invasion, vascular invasion, anaplasia, and eventually metastasis. This first mouse model of follicular thyroid carcinoma provides an unprecedented opportunity to study gene alterations during carcinogenesis. Indeed, using cDNA microarrays we have found altered expression of 20 named genes involved in tumor induction and progression, 16 named genes in invasion and metastasis, and 3 genes in cell proliferation and cell cycle regulation. We have also identified several altered signaling pathways that contribute to thyroid carcinogenesis of TR betaPV/PV mice. We have found that the peroxisome proliferator activated receptor can be tested as a potential molecular target for prevention and treatment of follicular thyroid carcinoma and that TR betaPV/PV mice can be used as a preclinical model for testing drugs. Discovery of TR betaPV/- mice as a second mouse model of thyroid carcinogenesis To identify other genetic changes in the TR beta gene that could also induce thyroid carcinoma, we prepared mice with mutation of one TR beta allele in the absence of the other wild-type allele (TR betaPV/- mice). As TR betaPV/- mice aged, they also spontaneously developed follicular thyroid carcinoma. The pathological progression of thyroid carcinoma in TR betaPV/- mice was indistinguishable from that in TR betaPV/PV mice. Analyses of the expression patterns of critical genes indicated activation of the signaling pathways mediated by thyroid stimulating hormone, peptide growth factors (epidermal growth factor and fibroblast growth factor), TGF-beta, TNF-alpha, and nuclear factor-kB. The gene profiling also suggested that the progressive repression of the pathways mediated by the peroxisome proliferator-activated receptor gamma could also contribute to the carcinogenesis of the thyroid. The patterns in the alteration of these signaling pathways are similar to those observed in TR betaPV/PV mice during thyroid carcinogenesis. These results indicate that in the absence of a wild-type allele, the mutation of one TR beta allele is sufficient for the mutant mice to develop follicular thyroid carcinoma spontaneously. These results provide for the first time in vivo evidence to suggest that the TR beta gene could function as a tumor suppressor gene. Importantly, these findings open the possibility that TR beta could serve as a novel therapeutic target in thyroid cancer. Identification of TR betaPV/PV mice as a model of pituitary tumorigenesis Thyrotropin (TSH)-secreting tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. More than 300 cases have been reported. TSHomas are usually large at diagnosis and are associated with headaches, visual field disturbances, and deficiency in other pituitary hormones. Because diagnosis occurs late in the natural course, the success rate of curative surgical resection of TSHomas remains under 50%. The molecular genetics underlying TSHomas are not well understood. Our discovery that TR betaPV/PV mice spontaneously develop TSHomas led to the first mouse model to elucidate molecular genetic events underlying tumorigenesis of the pituitary. Indeed, analysis of gene expression profiles by cDNA microarrays identified overexpression of cyclin D1 mRNA in TR betaPV/PV mice. In addition, the expression of cyclin D1 protein and other cell cycle regulators such as cyclin-dependent kinases (CDK4 and CDK6) is also increased. Importantly, the retinoblastoma protein (Rb) is hyper-phosphorylated in the pituitary of TR betaPV/PV mice. Thus, the activated cyclin D1/CDK/Rb/E2F pathway leads to aberrant proliferation of thyrotropes in the pituitary of TR betaPV/PV mice. Using a series of cyclin D1 promoter reporters, we further found that TR beta represses the expression of cyclin D1 by tethering to the cyclin D1 promoter through binding to the c-AMP response element binding protein. That repression effect is lost in mutant PV, thereby resulting in constitutive activation of cyclin D1 in TR betaPV/PV mice. Our study revealed a novel molecular mechanism by which an unliganded TR beta mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSHomas in patients.